Convenient method of synthesizing aryloxyalkyl esters from phenolic esters using halogenated alcohols

Article abstract of DOI:10.3390/molecules23071715

A facile one-pot synthetic method of building aryloxyalkyl esters was developed using various types of phenolic esters with halogenated alcohols. The ready availability of both starting materials, coupled with the required simple experimental technique, enables the current synthetic method of producing aryloxyalkyl esters in a fast and efficient way. It is noteworthy that acyl transfer was demonstrated in this reaction.

Full text of DOI:10.3390/molecules23071715

molecules
Article
Convenient Method of Synthesizing Aryloxyalkyl
Esters from Phenolic Esters Using
Halogenated Alcohols
Xueyang Jiang 1 ID , Junting Zhou 1, Yue Zhou 2 ID , Haopeng Sun 3, Jian Xu 1, Feng Feng 1,4,5,
*
and Wei Qu 1,4,
*
1
Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;
ajyang@stu.cpu.edu.cn (X.J.); zhoujunting0920@163.com (J.Z.); xujian201009@126.com (J.X.)
Department of Pharmacy Administration & Clinical Pharmacy, Peking University, Beijing 100191, China;
yuezhouzhy@163.com
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;
sunhaopeng@163.com
Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University,
Nanjing 210009, China
Food and Drug Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, China
Correspondence: fengfeng@cpu.edu.cn (F.F.); popoqzh@126.com (W.Q.); Tel.: +86-25-86185216 (F.F. & W.Q.)
2
3
4
5
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 22 June 2018; Accepted: 12 July 2018; Published: 13 July 2018
Abstract: A facile one-pot synthetic method of building aryloxyalkyl esters was developed using
various types of phenolic esters with halogenated alcohols. The ready availability of both starting
materials, coupled with the required simple experimental technique, enables the current synthetic
method of producing aryloxyalkyl esters in a fast and efficient way. It is noteworthy that acyl transfer
was demonstrated in this reaction.
Keywords: aryloxyalkyl esters; phenolic esters; acyl transfer
1. Introduction
Phenols are typically protected by various groups to enhance their leaving ability in cross-coupling
reactions [
electrophiles, such as fluoroalkylsulfonates [
carbamates [16 17], ethers [18], phosphoramides, phosphonium salts, phosphates, and pivalates [19
Besides the preferable availability of phenol derivatives, this method also proves to be cost-effective,
as well as an efficient reaction route to form C-C bonds, C-N bonds, and C-H bonds (Scheme 1) [23 28].
1–
3
]. Thus, phenols have usually been converted to their corresponding aryl C-O
], sulfamates [ ], sulfonates [ 12], carbonates [13 15],
22].
4
,
5
6–
8
9–
–
–
,
–
Phenolic esters, a type of aryl C-O electrophiles, are considered as notable functional groups or
protecting groups in organic synthesis, and can be found in various bioactive natural products,
agrochemicals, pharmaceuticals, and functional polymers [29–31].
Molecules 2018, 23, 1715; doi:10.3390/molecules23071715
www.mdpi.com/journal/molecules

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Scheme 1. The structures of C-O electrophiles and their subsequent conformation of C-C bonds,
C-N bonds, and C-H bonds.
To further the interest in the modification of flavonoids [32], we tried to synthesize
7-(3-hydroxypropoxy) wogonin by modifying the 7-acetate of wogonin with 3-bromoethanol.
Unfortunately, the desired product (7-hydroxypropoxy wogonite) was rarely obtained. Aryloxyalkyl
ester (3ba), however, was serendipitously obtained through the reaction displayed in Scheme 2.
Previous study has indicated that aryloxyalkyl esters were important moieties in organic syntheses,
primarily due to ubiquitous applications in pharmaceuticals, electrophosphorescent materials,
plasticizers, and luminescent materials [33
though a two-step process: Introduction of an aliphatic chain, followed by esterification with carboxylic
acids or anhydrides [37 38]. Undoubtedly, the efficiency of these protocols was restricted from the
–36]. The preparation of aryloxyalkyl esters was mainly
,
view of step economy for the synthesis of a variety of substituents. Herein, we disclose a convenient
synthesis of aryloxyalkyl esters from phenolic esters with halogenated alcohol.
Scheme 2. The new method to synthesize aryloxyalkyl ester.
2. Results and Discussion
First, we investigated the effects of reaction parameters in this new aryloxyalkyl esterification
reaction (Table 1). Phenyl acetate (1a) was chosen as a model substrate and subjected to a preliminary
condensation condition by using 3-bromoethanol (2a) (1.05 equiv) and K2CO3 (1.5 equiv) in
commercial grade acetone under reflux for 6 h. Gratifyingly, the phenolic ester extension reaction
proceeded smoothly, with concomitant cleavage of the ester bond and construction of the ether bond,
delivering 3-phenoxypropyl acetate (3aa) in 59% isolated yield (entry 1). Changing the solvent from
acetone to tetrahydrofuran or acetonitrile resulted in inferior results (entries 2 and 3). However,
when N,N-dimethylformamide (DMF) was used as the solvent, 3aa was obtained in comparably good
conversions (entry 4). By increasing the amount of potassium carbonate, further enhancive conversion
was observed, which have been used to establish the optimal conditions (entry 5). No reaction was
observed without a base (entry 6), whereas a weak base depressed the conversion (entry 7), indicating
that the base could break the ester bond. Two other bases, i.e., Cs2CO3 and NaH, afforded the products
(entries 8 and 9) with similar yields to entry 5. When NaOH was used as the base, only a trace
amount of the target product, 3aa, was detected by high performance liquid chromatography (HPLC),
instead of generating a large amount of 3-phenoxypropan-1-ol. (entry 10).

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a
Table 1. Condition optimization for aryloxyalkyl esterification.
Yield (%) b
Entry
Base
Equiv
Solvent
Temp.
◦
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1.5
1.5
1.5
1.5
3
–
3
3
3
1.5
acetone
THF
60 C
59
51
54
65
72
◦
60 C
◦
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
60 C
◦
80 C
◦
80 C
c
◦
NR d
13
76
73
–
80 C
◦
KHCO3
Cs2CO3
NaH
80 C
◦
80 C
◦
60 C
◦
10
NaOH
60 C
Trace
a
Reaction conditions: Except where otherwise noted, all of the reactions were performed with 1a (0.5 mmol),
b
2a (0.525 mmol), and a base in the solvent (1.5 mL) for 6 h under an Ar atmosphere. Yield of isolated product.
c
d
–: No base exists. NR: No reaction. Thin layer chromatography (TLC) showed the presence of starting materials,
1a, and detected no new product.
Next, we investigated the application range of this reaction by using a variety of phenol esters
and bromoalkyl alcohols under the optimized conditions: 0.5 mmol of
1 and 0.525 mmol of 2 in DMF
at 80 ◦C for 6 h under an Ar atmosphere (Scheme 3). Both electron-rich and electron-withdrawing
substituents produced the desired aryloxyalkyl esters in good yields (3ab and 3ac). It is noteworthy
that substrates bearing functional groups (e.g., aldehyde, ketone, nitrile, or halogen) also showed
good performance in this reaction (3ad–ai). To further extend the utility of this reaction, we then
put our effort to the types of acid esters from the common acetates. It was observed that various
substituted phenyl benzoates reacted well, leading to the formation of the corresponding aryloxyalkyl
esters (3aj–an) in yields of 47–71%. Notably, chlorophenylacetate moiety was tolerated, providing the
target product, 3ao, in 45% yield. Delightfully, we found that even cinnamate derivatives under the
reaction conditions could give the corresponding products (3ap and 3aq) in moderate to good yields
(with increased base loading). Changing the starting material from phenyl ester to alkyl ester, however,
resulted in a large amount of alkyl ester remaining and no target product, which might be because the
ester bond of alkyl ester was difficult to be broken (see Scheme S1 in Supplementary Materials).
Furthermore, the diversity of halohydrins was also studied (Scheme 4). 2-Bromoethanol (2b),
4-bromobutanol (2c), and 5-bromopentanol (2d) performed similarly to produce the corresponding
products, 3ar–ax, in moderate to high yields. For the synthesis of compound 3ar, the usage of
2-bromoethanol, 2-chloroethanol, or 2-iodoethanol contributed similar yields, wherein the use of
2-iodoethanol slightly increased the yield of 3ar. The longer alkyl chain resulted in lower yield.
The scope of the present investigation was extended to flavone derivatives. Baicalein and wogonin
were applicable under our reaction conditions, providing the target products (3ay, 3az and 3ba) in
moderate yields.

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Scheme 3. Scope of the reaction of phenol esters.
Scheme 4. Scope of the reaction of halogenated alcohols and application to the synthesis of
flavonoid derivatives.

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A series of control experiments were carried out to elucidate the reaction mechanism (Scheme 5).
Firstly, as 3-methyl-2-butenyl bromide (2e) was used to substitute 3-bromoethanol (2a), the product,
1-isopentenyl naphthol (
when the amount of 3-bromopropanol (2a) was increased from 1.05 equivalents to 4 equivalents,
3-(2-naphthoxy)propan-1-ol ( ) was obtained, which suggested that the generated acetyl reactive
4), was obtained instead of the target product (Scheme 5A). Secondly,
5
intermediate might not be selective in reacting with the alcoholic hydroxyl group (Scheme 5B).
No reaction was observed when no potassium carbonate was used, indicating that the phenolic
ester bond was firstly broken by potassium carbonate. Further, sulfonates and aromatic amides were
found to be incompatible with the reaction conditions and resulted in nothing even under refluxing
conditions, suggesting that potassium carbonate could not attack the carbonyl group of the acylamine
bonds because the polarization of the carbonyl group is weaker compared with the ester carbonyl
group (Scheme 5C,D). However, when the strong base, NaH, was used, the deprotonation of 2a formed
an oxygen negative intermediate, which would attack the carbonyl group at a high temperature.
Scheme 5. Control experiments to investigate the mechanism.
Based on the above experiments, we propose a plausible mechanism as shown in Scheme 4.
Initially, in the presence of potassium carbonate (Scheme 6A), phenyl acetate (1a) is transformed
into phenol salt
8
and intermediate
9, exhibiting similar chemical properties with anhydrides [39].
Subsequently, the two-step reaction is carried out separately. On one hand, phenol salt
8
is allowed
to react with bromopropanol to form a phenolic ester by SN2 nucleophilic substitutions. On the
other hand, propanol OH with a nucleophilicity can attack the carbonyl carbon of the intermediate
9
, and release a molecule of potassium bicarbonate to form an ester bond. To verify the speculation
that this reaction had two separate steps, intermediate was employed to react with acetic anhydride
5
(1 equiv), which could be transformed to 3ah in an isolated yield of 73%. The 1-butanol (2f) was used
to react with substrate 1v under the standard conditions, resulting in the products 10 and 11. Based on
these observations, we came to the conclusion that the oxygen atom of the alcoholic hydroxyl group
attacked the carbonyl carbon atom to form the ester bond. Additionally, when NaH was used as a base,
the reaction might be carried out according to the following route (Scheme 6B): In the presence of
NaH, 3-bromopropanol (2a) deprotonated to form the oxygen negative intermediate, 12, which then
nucleophilically attacked the phenolic ester bond of the compound, 1a, to form the intermediates,
13 and 14. Subsequently, intermediates 13 and 14 underwent a SN2 nucleophilic substitution reaction
to produce the target compound, 3aa.

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Scheme 6. Proposed mechanism for the synthesis of aryloxyalkyl ester derivatives in the presence of
potassium carbonate (A), or in the presence of NaH (B).
Given the low selectivity of the intermediate
9 reacting with the alcoholic hydroxyl group,
we wondered whether the hydroxyl group in the own phenolic ester structure would also be reactive
substrates without additional halogenated alcohols. 5-Acetyl wogonin was used as a substrate to
study the intramolecular nucleophilic substitution reaction (Scheme 7). Gratifyingly, the desired target
product, 7-acetyl wogonin, was obtained in good yields without 5-acetyl wogonin remaining under
standard conditions. A possible explanation for the acyl transfer phenomenon was that the acetyl
group was detached from the 5-O-wogonin in the presence of potassium carbonate, subsequently
attacked by the highly nucleophilic 7-OH of wogonin to give 7-acetyl wogonin. The reason might be
the formation of the intramolecular hydrogen bond at 5-position with para-carbonyl group endowed it
with weaker acidity than 7-OH of wogonin, leading the acetyl group to easily binding to 7-OH.
Scheme 7. The acyl of 5-O-wogonin was transferred to the 7-position, forming 7-acetyl wogonin in the
presence of potassium carbonate.
3. Materials and Methods
3.1. General
All reactions were monitored by thin layer chromatography (TLC) on WhatmanPartisil® K6F
TLC plates (silica gel 60 Å, 0.25 mm thickness, Qingdao Haiyang Chemical Plant, Qingdao, China)
and visualized using a UV lamp (254 or 365 nm, Shanghai Guanghao Analysis Instrument Co., Ltd.,
Shanghai, China) or by use of one of the following visualization reagents: Products were isolated by
column chromatography (Merck silica gel 100–200 mesh, Merck, Darmstadt, Germany). Yields refer to
1
chromatographically and spectroscopically homogenous materials unless noted otherwise. H- and
13C-NMR spectra were recorded on Bruker 300 MHz spectrometers (Bruker, Karlsruhe, Germany).
3.2. General Procedure for the Aryloxyalkyl Esters from Phenolic Esters (3aa–3aq)
Phenyl esters 1a–1c (0.5 mmol) were loaded into a flask (10 mL). DMF (2 mL) and Cs2CO3 (488 mg,
1.5 mmol, 3.0 equiv) were then added, which was followed by th◦e addition of 3-bromoethanol (2a
,
0.525 mmol, 1.05 equiv). Then the reaction mixture was stirred at 80 C for 6 h under an Ar atmosphere.

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After completion of the reaction, as confirmed by TLC, the reaction mixture was cooled down to room
temperature and 10 mL of CH2Cl2 (DCM) and 10 mL of water were added. After separation of the
dichloromethane layer from the water, the aqueous phase was extracted with CH2Cl2 (2 × 5 mL) again.
The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated
under vacuum to yield the crude product. The crude product was purified by silica gel column
chromatography to obtain the desired pure compound.
3-Phenoxypropyl acetate (3aa). Compound 3aa (CAS: 58883-98-0) was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 200:1)
to provide the pure compound (73 mg, 76%) as a colorless oil. 1H-NMR (300 MHz, CDCl3,
δ ppm): 7.33 (t, J = 8.2 Hz, 2H), 6.93–6.99 (m, 1H), 6.93 (d, J = 8.6 Hz, 2H), 4.31 (t, J = 6.1 Hz, 2H),
4.07 (t, J = 6.1 Hz, 2H), 2.13–2.19 (m, 2H), 2.09 (s, 3H); 13C-NMR (75 MHz, CDCl3,
129.1, 120.3, 113.9, 63.6, 60.9, 28.1, 20.4; MS (ESI): m/z = 193.1 [M
H]−; Rf = 0.5 (DCM:MeOH 100:1).
δ ppm): 170.7, 158.2,
−
3-(4-Methoxyphenoxy)propyl acetate (3ab). Compound 3ab was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 200:1)
1
to provide the pure compound (71 mg, 64%) as a colorless oil. H-NMR (300 MHz, CDCl3, δ ppm):
6.85 (s, 4H, Ar-H), 4.27 (t, J = 6.1 Hz, 2H), 4.01 (t, J = 6.1 Hz, 2H), 3.78 (s, 3H, -OCH3), 2.08–2.14 (m, 2H)
,
2.07 (s, 3H, -COCH3); δ ppm): 196.8, 171.0, 162.6, 130.6, 130.4, 114.1, 64.6,
13C-NMR (75 MHz, CDCl3,
61.0, 28.4, 26.3, 20.9; HRMS (ESI): m/z calcd. for C12H17O4: 225.1121, found: 225.1119 [M + H]+
;
Rf = 0.5 (DCM:MeOH 100:1).
3-(4-Nitrophenoxy)propyl acetate (3ac). Compound 3ac (CAS: 99986-51-3) was prepared following the
general procedure described above and purified by silica gel column chromatography (DCM:MeOH
1
100:1) to provide the pure compound (96 mg, 81%) as a light yellow oil. H-NMR (300 MHz, CDCl3,
δ ppm): 8.17 (d, J = 8.1 Hz, 2H), 6.5 (d, J = 8.1 Hz, 2H), 4.26 (t, J = 6.1 Hz, 2H), 4.14 (t, J = 6.1 Hz, 2H)
,
2.12–2.20 (m, 2H), 2.05 (s, 3H); 13C-NMR (75 MHz, CDCl3,
δ ppm): 170.4, 163.2, 140.9, 125.3, 113.9, 64.7,
60.3, 27.8, 20.4; MS (ESI): m/z = 238.1 [M − H]−; Rf = 0.2 (DCM:MeOH 100:1).
3-(4-Formylphenoxy)propyl acetate (3ad). Compound 3ad was prepared following the general procedure
described above and purified by silica gel column chromatography (DCM:MeOH 50:1) to provide the
1
pure compound (54 mg, 49%) as a colorless oil. H-NMR (300 MHz, CDCl3, δ ppm)
:
9.83 (s, 1H, -CHO)
,
,
7.78 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.1 Hz, 2H), 4.11 (t, J = 6.1 Hz, 2H)
2.02 (s, 3H, -COCH3), 1.77–1.89 (m, 2H); 13C-NMR (75 MHz, CDCl3,
, 4.04 (t, J = 6.1 Hz, 2H)
δ
ppm): 190.3, 170.6, 163.4,
131.5, 129.3, 114.1, 67.1, 63.4, 24.7, 20.4; MS (ESI): m/z = 221.1 [M
−
H]−; HRMS (ESI): m/z calcd. for
C12H15O4: 223.0965, found: 223.0961 [M + H]+; Rf = 0.3 (DCM:MeOH 50:1).
3-(4-Acetylphenoxy)propyl acetate (3ae). Compound 3ae (CAS: 146274-20-6) was prepared following the
general procedure described above and purified by silica gel column chromatography (DCM:MeOH
100:1) to provide the pure compound (66 mg, 57%) as a colorless oil. 1H-NMR (300 MHz, CDCl3,
δ ppm): 7.94 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 4.27 (t, J = 6.1 Hz, 2H), 4.12 (t, J = 6.1 Hz, 2H)
2.56 (s, 3H), 2.13–2.17 (m, 2H), 2.06 (s, 3H); 13C-NMR (75 MHz, CDCl3,
ppm): 196.8, 171.0, 162.7, 130.6,
130.4, 114.1, 64.6, 61.0, 28.4, 26.3, 20.9; MS (ESI): m/z = 235.1 [M + H]+; Rf = 0.3 (DCM:MeOH 100:1).
,
δ
3-(4-Cyanophenoxy)propyl acetate (3af). Compound 3af was prepared following the general procedure
described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide
the pure compound (86 mg, 79%) as a colorless oil. 1H-NMR (300 MHz, CDCl3,
δ
ppm):
7.58 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 4.26 (t, J = 6.1 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H),
2.07–2.18 (m, 2H), 2.04 (s, 3H); δ ppm): 161.5, 150.4, 133.4, 118.6, 114.6,
13C-NMR (75 MHz, CDCl3,
103.5, 64.2, 60.4, 27.8, 20.4; HRMS (ESI): m/z calcd. for C12H14NO4: 220.0968, found: 220.0972 [M + H]+
;
Rf = 0.3 (DCM:MeOH 100:1).
3-([1,10-Biphenyl]-4-yloxy)propyl acetate (3ag). Compound 3ag (CAS: 1417800-59-9) was prepared
following the general procedure described above and purified by silica gel column chromatography

Molecules 2018, 23, 1715
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(DCM:MeOH 100:1) to provide the pure compound (94 mg, 70%) as a light yellow solid.
1H-NMR (300 MHz, CDCl3,
ppm): 7.58 (d, J = 8.2 Hz, 2H), 7.47 (t, J = 6.2 Hz, 2H), 7.34–7.41 (m, 3H),
7.10 (t, J = 8.2 Hz, 1H), 7.05 (t, J = 8.2 Hz, 1H), 4.22 (t, J = 6.1 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 2.09–2.13
(m, 2H), 2.05 (s, 3H) ppm): 170.5, 155.1, 137.9, 130.5, 129.0, 128.1, 127.4,
13C-NMR (75 MHz, CDCl3,
126.4, 120.7, 112.1, 64.3, 60.8, 28.1, 20.4; MS (ESI): m/z = 293.2 [M + Na]+; Rf = 0.5 (DCM:MeOH 100:1)
δ
;
δ
.
3-(Naphthalen-2-yloxy)propyl acetate (3ah). Compound 3ah (CAS: 1174495-88-5) was prepared following
the general procedure described above and purified by silica gel column chromatography (DCM:MeOH
100:1) to provide the pure compound (83 mg, 68%) as a yellow solid. 1H-NMR (300 MHz, CDCl3,
δ ppm): 7.78–7.84 (m, 3H), 7.51 (t, J = 6.2 Hz, 1H), 7.40 (t, J = 6.2 Hz, 1H), 7.18–7.23 (m, 2H)
4.36 (t, J = 6.1 Hz, 2H), 4.17 (t, J = 6.1 Hz, 2H), 2.17–2.25 (m, 2H), 2.12 (s, 3H); 13C-NMR (75 MHz
,
,
CDCl3, δ ppm): 170.6, 156.3, 134.1, 129.0, 128.5, 127.2, 126.3, 125.9, 123.2, 118.4, 106.1, 63.8, 60.92,
28.1, 20.5; MS (ESI): m/z = 243.1 [M − H]−; Rf = 0.6 (DCM:MeOH 100:1).
3-(4-Chlorophenoxy)propyl benzoate (3ai). Compound 3ai was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1)
to provide the pure compound (71 mg, 49%) as a light yellow solid. 1H-NMR (300 MHz, CDCl3,
δ ppm): 8.08 (d, J = 8.2 Hz, 2H), 7.58 (t, J = 6.2 Hz, 1H), 7.46 (t, J = 6.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H),
6.85 (d, J = 8.2 Hz, 2H), 4.55 (t, J = 6.1 Hz, 2H), 4.11 (t, J = 6.1 Hz, 2H), 2.23–2.31 (m, 2H);
13C-NMR (75 MHz, CDCl3,
δ ppm): 165.9, 156.9, 132.5, 129.6, 129.0, 128.8, 127.9, 125.1, 115.2, 64.3,
61.2, 28.2; HRMS (ESI): m/z calcd. for C16H16ClO3: 291.0782, found: 291.0779 [M + H]+; Rf = 0.3
(DCM:MeOH 100:1).
3-(4-Formylphenoxy)propyl benzoate (3aj). Compound 3aj (CAS: 864845-56-7) was prepared following the
general procedure described above and purified by silica gel column chromatography (DCM:MeOH
50:1) to provide the pure compound (67 mg, 47%) as a yellow solid. 1H-NMR (300 MHz, CDCl3,
δ ppm): 9.88 (s, 1H, -CHO), 8.04 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.57 (t, J = 6.2 Hz, 1H)
,
7.42 (t, J = 8.2 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 4.54 (t, J = 6.1 Hz, 2H), 4.22 (t, J = 6.1 Hz, 2H), 2.26–2.33
(m, 2H); δ ppm): 190.3, 159.2, 132.5, 131.5, 129.0, 127.9, 114.2, 64.4, 61.0,
13C-NMR (75 MHz, CDCl3,
28.1; MS (ESI): m/z = 283.1 [M − H]−; Rf = 0.2 (DCM:MeOH 50:1).
3-(4-Cyanophenoxy)propyl benzoate (3ak). Compound 3ak was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1)
1
to provide the pure compound (100 mg, 71%) as yellow solids. H-NMR (300 MHz, CDCl3, δ ppm):
8.07 (d, J = 8.6 Hz, 2H), 7.61 (t, J = 6.2 Hz, 1H), 7.46 (t, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H)
,
;
6.86 (d, J = 8.2 Hz, 2H), 4.55 (t, J = 6.1 Hz, 2H), 4.11 (t, J = 6.1 Hz, 2H), 2.23–2.32 (m, 2H)
13C-NMR (75 MHz, CDCl3, δ ppm): 165.8, 161.5, 133.4, 132.5, 129.5, 129.0, 127.9, 118.7, 114.7, 103.4,
64.4, 61.0, 28.0; HRMS (ESI): m/z calcd. for C17H16NO3: 282.1125, found: 282.1129 [M + H]+
; Rf = 0.6
(DCM:MeOH 50:1).
3-(Naphthalen-2-yloxy)propyl benzoate (3al). Compound 3al was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to
1
provide the pure compound (99 mg, 65%) as yellow solids. H-NMR (300 MHz, DMSO-d6,
δ ppm):
1H-NMR (300 MHz, CDCl3,
δ
ppm): 8.05 (d, J = 8.6 Hz, 2H), 7.78–7.85 (m, 3H), 7.60 (t, J = 6.2 Hz, 1H)
7.51 (t, J = 6.2 Hz, 1H), 7.37 (t, J = 6.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H)
4.62 (t, J = 6.1 Hz, 2H), 4.29 (t, J = 6.1 Hz, 2H), 2.31–2.40 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm)
,
,
:
166.1, 162.4, 133.9, 131.7, 129.1, 128.2, 127.6, 127.1, 126.8, 126.2, 123.6, 122.7, 118.9, 113.2, 106.3,
63.8, 61.4, 27.9; HRMS (ESI): m/z calcd. for C20H19O3: 307.1329, found: 307.1335 [M + H]+
; Rf = 0.4
(DCM:MeOH 100:1).
3-(Naphthalen-2-yloxy)propyl 4-methoxybenzoate (3am). Compound 3am was prepared following the
general procedure described above and purified by silica gel column chromatography (DCM:MeOH
1
100:1) to provide the pure compound (114 mg, 68%) as yellow solids. H-NMR (300 MHz, CDCl3,
δ ppm): 8.07 (d, J = 8.6 Hz, 2H), 7.76–7.83 (m, 3H), 7.49 (t, J = 6.2 Hz, 1H), 7.39 (t, J = 6.2 Hz, 1H),

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7.23 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.2 Hz, 2H), 4.60 (t, J = 6.1 Hz, 2H), 4.27 (t, J = 6.1 Hz, 2H),
3.86 (s, 3H, -OCH3), 2.36–2.42 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 165.8, 162.9, 156.3, 134.1,
131.2, 129.0, 128.5, 127.2, 126.3, 125.9, 123.2, 122.1, 118.5, 113.2, 106.1, 64.0, 61.1, 54.9, 28.3; HRMS (ESI)
m/z calcd. for C21H21O4: 337.1434, found: 337.1431 [M + H]+; Rf = 0.3 (DCM:MeOH 100:1).
:
3-(Naphthalen-2-yloxy)propyl 4-nitrobenzoate (3an). Compound 3an was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 50:1)
1
to provide the pure compound (108 mg, 62%) as yellow solids. H-NMR (300 MHz, CDCl3, δ ppm):
8.28 (d, J = 8.6 Hz, 2H), 8.21 (d, J = 8.6 Hz, 2H), 7.72–7.80 (m, 3H), 7.46 (t, J = 6.2 Hz, 1H),
7.37 (t, J = 6.2 Hz, 1H)
,
7.17 (d, J = 8.2 Hz, 2H), 4.66 (t, J = 6.1 Hz, 2H), 4.28 (t, J = 6.1 Hz, 2H), 2.36–2.42
ppm): 164.1, 156.1, 149.9, 133.9, 130.5, 130.2, 129.0, 128.5, 127.1,
(m, 2H)
;
13C-NMR (75 MHz, CDCl3,
δ
126.2, 125.9, 123.2, 123.0, 118.2, 106.0, 63.7, 62.4, 28.1; HRMS (ESI): m/z calcd. for C20H18NO5: 352.1179,
found: 352.1175 [M + H]+; Rf = 0.2 (DCM:MeOH 100:1).
3-(4-Formylphenoxy)propyl 2-(2-chlorophenyl)acetate (3ao). Compound 3ao was prepared following the
general procedure described above and purified by silica gel column chromatography (DCM:MeOH
1
50:1) to provide the pure compound (74 mg, 45%) as yellow solids. H-NMR (300 MHz, CDCl3, δ ppm):
9.87 (s, 2H, -CHO), 7.83 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 6.2 Hz, 1H), 7.26–7.29 (m, 1H), 7.19–7.23 (m, 2H),
6.96 (d, J = 8.2 Hz, 2H), 4.33 (t, J = 6.1 Hz, 2H), 4.06 (t, J = 6.1 Hz, 2H), 3.78 (s, 2H), 2.12–2.16 (m, 2H)
;
13C-NMR (75 MHz, CDCl3,
δ
ppm): 190.2, 169.9, 163.2, 131.8, 131.4, 130.9, 129.5, 129.4, 128.9, 128.2,
126.4, 114.2, 64.0, 60.9, 38.7, 27.8; HRMS (ESI): m/z calcd. for C18H18ClO4: 333.0888, found: 333.0892
[M + H]+; Rf = 0.4 (DCM:MeOH 50:1).
3-(4-Cyanophenoxy)propyl (E)-3-(4-chlorophenyl)acrylate (3ap). Compound 3ap was prepared following
the general procedure described above and purified by silica gel column chromatography (DCM:MeOH
40:1) to provide the pure compound (71 mg, 42%) as yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm):
7.63 (d, J = 15.6 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H)
6.95 (d, J = 8.1 Hz, 2H), 6.39 (d, J = 15.6 Hz, 1H), 4.40 (t, J = 6.1 Hz, 2H), 4.13 (t, J = 6.1 Hz, 2H), 2.17–2.6
(m, 2H) ppm): 166.5, 162.0, 143.6, 136.2, 133.9, 132.7, 129.2, 129.1, 119.2,
13C-NMR (75 MHz, CDCl3,
,
;
δ
118.3, 115.1, 104.0, 64.8, 61.3, 28.4; HRMS (ESI): m/z calcd. for C19H17ClNO3: 342.0891, found: 342.0896
[M + H]+; Rf = 0.3 (DCM:MeOH 50:1).
3-(Naphthalen-2-yloxy)propyl cinnamate (3aq). Compound 3aq was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 50:1) to
1
provide the pure compound (84 mg, 51%) as yellow solids. H-NMR (300 MHz, DMSO-d6,
δ ppm):
1H-NMR (300 MHz, CDCl3, δ ppm): 7.74–7.85 (m, 4H), 7.53–7.59 (m, 2H), 7.49 (t, J = 6.2 Hz, 1H)
7.36–7.47 (m, 4H), 7.20–7.24 (m, 2H), 6.52 (d, J = 15.6 Hz, 1H), 4.53 (t, J = 6.1 Hz, 2H),
4.27 (t, J = 6.1 Hz, 2H), 2.27–2.37 (m, 2H); 13C-NMR (75 MHz, CDCl3,
ppm): 166.5, 156.3, 144.5,
,
δ
134.1, 133.8, 129.8, 128.9, 128.4, 127.6, 127.3, 127.2, 126.3, 125.9, 123.2, 118.4, 117.5, 106.1, 63.9, 61.0, 28.3;
HRMS (ESI): m/z calcd. for C22H21O3: 333.1485, found: 333.1487 [M + H]+; Rf = 0.4 (DCM:MeOH 50:1).
3.3. General Procedure for the Reaction of Halogenated Alcohols and Application to the Synthesis of Flavonoid
Derivatives (3ar–3ba)
Phenyl esters 1a–1j (0.5 mmol) were loaded into a flask (10 mL). DMF (4 mL) and Cs2CO3
(488 mg, 1.5 mmol, 3.0 equiv) were then added, which was followed by the addition of bromohydrin
◦
(0.525 mmol, 1.05 equiv). Then, the reaction mixture was stirred at 80 C for 6 h under an Ar atmosphere.
After completion of the reaction, as confirmed by TLC, the reaction mixture was cooled down to room
temperature and 10 mL of EtOAc and 10 mL of water were added. After separation of the EtOAc layer
from the water, the aqueous phase was extracted with EtOAc (2
×
5 mL) again. The combined organic
layers were then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to yield the
crude product. The crude product was purified by silica gel column chromatography to obtain the
desired pure compound.

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2-(4-Formylphenoxy)ethyl acetate (3ar). Compound 3ar (CAS: 151270-72-3) was prepared following the
general procedure described above and purified by silica gel column chromatography (DCM:MeOH
100:1) to provide the pure compound (76 mg, 73%) as a colorless oil. 1H-NMR (300 MHz, CDCl3,
δ ppm): 9.84 (s, 1H, -CHO), 7.79 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H),
4.22 (t, J = 6.1 Hz, 2H), 2.06 (s, 3H); 13C-NMR (75 MHz, CDCl3,
δ ppm): 170.2, 162.8, 131.3, 129.6, 121.8,
114.2, 65.6, 61.8, 20.2; MS (ESI): m/z = 207.1 [M − H]−; Rf = 0.3 (DCM:MeOH 50:1).
2-(4-Cyanophenoxy)ethyl acetate (3as). Compound 3as (CAS: 150195-05-4) was prepared following the
general procedure described above and purified by silica gel column chromatography (DCM:MeOH
100:1) to provide the pure compound (79 mg, 77%) as a colorless oil. 1H-NMR (300 MHz, CDCl3,
δ ppm): 7.56 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H), 4.20 (t, J = 6.1 Hz, 2H)
,
2.07 (s, 3H); 13C-NMR (75 MHz, CDCl3,
δ ppm): 170.3, 161.2, 133.4, 118.5, 114.7, 103.7, 65.6, 61.7, 20.3;
MS (ESI): m/z = 204.1 [M − H]−; Rf = 0.3 (DCM:MeOH 100:1).
2-(4-Formylphenoxy)ethyl benzoate (3at). Compound 3at was prepared following the general procedure
described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the
1
pure compound (94 mg, 70%) as a colorless oil. H-NMR (300 MHz, CDCl3,
δ
ppm): 9.91 (s, 1H, -CHO)
,
8.07 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.59 (t, J = 8.1 Hz, 1H), 7.43–7.48 (m, 2H)
,
7.07 (d, J = 8.1 Hz, 2H), 4.72 (t, J = 6.1 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H); 13C-NMR (75 MHz, CDCl3,
δ ppm): 165.9, 163.0, 132.7, 131.9, 131.5, 129.8, 129.2, 127.9, 115.8, 114.3, 65.7, 62.4; HRMS (ESI):
m/z calcd. for C16H15O4: 271.0965, found: 271.0971 [M + H]+; Rf = 0.2 (DCM:MeOH 50:1).
2-(Naphthalen-1-yloxy)ethyl 4-methoxybenzoate (3au). Compound 3au was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to
1
provide the pure compound (104 mg, 65%) as light yellow solids. H-NMR (300 MHz, CDCl3,
δ ppm):
8.10 (d, J = 8.1 Hz, 2H), 7.77–7.84 (m, 3H), 7.51 (t, J = 8.1 Hz, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.25 (m, 1H)
6.93 (d, J = 8.1 Hz, 2H), 4.75 (t, J = 6.1 Hz, 2H), 4.42 (t, J = 6.1 Hz, 2H), 3.85 (s, 3H, -OCH3)
13C-NMR
(75 MHz, CDCl3, ppm): 166.3, 163.5, 156.6, 134.5, 131.8, 129.6, 129.1, 127.7, 126.8, 126.5, 123.9, 122.3,
,
;
δ
118.9, 113.7, 106.9, 66.1, 63.2, 55.4; HRMS (ESI): m/z calcd. for C20H19O4: 323.1278, found: 323.1273
[M + H]+; Rf = 0.4 (DCM:MeOH 50:1).
4-(Naphthalen-1-yloxy)butyl 4-methoxybenzoate (3av). Compound 3av was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1)
to provide the pure compound (89 mg, 51%) as light yellow solids. 1H-NMR (300 MHz, CDCl3,
δ ppm): 8.02 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H)
7.36 (t, J = 8.1 Hz, 1H) 7.18 (m, 1H) 6.91 (d, J = 8.2 Hz, 2H)
3.86 (s, 3H, -OCH3), 2.03–2.05 (m, 4H); 13C-NMR (75 MHz, CDCl3,
,
7.73 (d, J = 8.1 Hz, 2H)
4.43 (t, J = 6.1 Hz, 2H)
ppm): 165.9, 162.8, 156.3, 147.0, 134.0,
,
,
7.46 (t, J = 8.1 Hz, 1H)
4.18 (t, J = 6.1 Hz, 2H),
,
,
,
,
δ
131.0, 128.9, 127.1, 126.2, 125.8, 123.0, 122.2, 118.4, 113.0, 106.1, 66.8, 63.9, 54.9, 25.5, 25.1; HRMS (ESI):
m/z calcd. for C22H23O4: 351.1591, found: 351.1587 [M + H]+; Rf = 0.4 (DCM:MeOH 50:1).
4-(4-Chlorophenoxy)butyl acetate (3aw). Compound 3aw was prepared following the general procedure
described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide
the pure compound (65 mg, 54%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm):
7.23 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.2 Hz, 2H), 4.15 (t, J = 6.1 Hz, 2H), 3.95 (t, J = 6.1 Hz, 2H),
2.07 (s, 3H), 1.82–1.86 (m, 4H); 13C-NMR (75 MHz, CDCl3,
δ ppm): 157.0, 128.7, 124.9, 116.1, 115.2, 67.0,
63.6, 25.2, 24.8, 20.4; HRMS (ESI): m/z calcd. for C12H16O3Cl: 243.0782, found: 243.0786 [M + H]+;
Rf = 0.5 (DCM:MeOH 100:1).
5-(4-Cyanophenoxy)pentyl benzoate (3ax). Compound 3ax was prepared following the general
procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1)
to provide the pure compound (60 mg, 39%) as a colorless oil. 1H-NMR (300 MHz, CDCl3,
δ ppm): 8.05 (d, J = 8.2 Hz, 2H), 7.55–7.59 (m, 3H), 7.45 (t, J = 6.3 Hz, 1H), 6.94 (d, J = 8.2 Hz, 2H)
,
,
4.38 (t, J = 6.1 Hz, 2H), 4.04 (t, J = 6.1 Hz, 2H), 1.83–1.95 (m, 4H), 1.60–1.70 (m, 2H); 13C-NMR (75 MHz

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CDCl3, δ ppm): 166.6, 162.2, 133.9, 132.9, 129.5, 128.3, 119.3, 115.1, 68.0, 64.6, 28.6, 28.4, 22.6; HRMS (ESI):
m/z calcd. for C19H20O3N: 310.1438, found: 310.142 [M + H]+; Rf = 0.6 (DCM:MeOH 50:1).
((5-Hydroxy-4-oxo-2-phenyl-4H-chromene-6,7-diyl)bis(oxy))bis(propane-3,1-diyl) diacetate (3ay). Compound
3ay was prepared from 6,7-diacetyl baicalein following the general procedure described above
and purified by silica gel column chromatography (DCM:MeOH 50:1) to provide the pure
1
compound (110 mg, 47%) as yellow solids. H-NMR (300 MHz, CDCl3,
δ ppm): 12.67 (s, 1H, -OH),
7.90 (d, J = 8.1 Hz, 2H), 7.51–7.60 (m, 3H), 6.69 (s, 1H), 6.57 (s, 1H), 4.37 (t, J = 6.1 Hz, 2H),
4.33 (t, J = 6.1 Hz, 2H)
,
4.18 (t, J = 6.1 Hz, 2H), 4.15 (t, J = 6.1 Hz, 2H), 2.21–2.30 (m, 2H), 2.13 (m, 2H)
,
;
2.10 (s, 3H), 2.08 (s, 3H); HRMS (ESI): m/z calcd. for C25H27O9: 471.1650, found: 471.1659 [M + H]+
Rf = 0.6 (DCM:MeOH 30:1).
2-((5,6-Dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)ethyl acetate (3az). Compound 3az was prepared
from 7-acetyl baicalein following the general procedure described above and purified by silica gel
column chromatography (DCM:MeOH 40:1) to provide the pure compound (76 mg, 43%) as yellow
1
solids. H-NMR (300 MHz, DMSO-d6,
δ ppm): 12.53 (s, 1H, -OH), 8.81 (s, 1H, -OH), 8.06–8.11 (m, 2H),
7.55–7.63 (m, 3H), 7.00 (s, 1H), 6.98 (s, 1H), 4.39 (t, J = 6.1 Hz, 2H), 4.35 (t, J = 6.1 Hz, 2H), 2.07 (s, 3H);
13C-NMR (75 MHz, DMSO-d6,
δ
ppm): 182.2, 170.3, 163.1, 153.2, 149.5, 146.2, 131.9, 130.7, 130.2, 129.0,
126.2, 105.4, 104.6, 92.1, 66.9, 62.2, 20.6; HRMS (ESI): m/z calcd. for C19H17O7: 357.0969, found: 357.0975
[M + H]+; Rf = 0.3 (DCM:MeOH 30:1).
3-((5-Hydroxy-8-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)propyl acetate (3ba). Compound 3ba was
prepared from 7-acetyl wogonin following the general procedure described above and purified by
silica gel column chromatography (DCM:MeOH 50:1) to provide the pure compound (132 mg, 69%)
as yellow solids. 1H-NMR (300 MHz, CDCl3,
δ
ppm): 12.56 (s, 1H, -OH), 7.95 (t, J = 6.1 Hz, 2H),
7.55 (m, 3H), 6.69 (s, 1H), 6.44 (s, 1H), 4.33 (t, J = 6.1 Hz, 2H), 4.19 (t, J = 6.1 Hz, 2H), 3.94 (s, 3H, -OCH3),
2.19–2.28 (m, 2H), 2.10 (s, 3H); 13C-NMR (75 MHz, CDCl3,
ppm): 182.7, 178.0, 164.1, 163.9, 157.9, 1574,
δ
157.3, 131.9, 131.2, 129.1, 126.3, 126.2, 105.3, 96.5, 65.5, 61.6, 60.9, 28.4, 20.9; HRMS (ESI): m/z calcd. for
C21H21O7: 385.1282, found: 385.1278 [M + H]+; Rf = 0.3 (DCM:MeOH 50:1).
3.4. Control Experiments to Investigate the Mechanism
2-((3-Methylbut-2-en-1-yl)oxy)naphthalene (4). Phenyl esters 1i (0.5 mmol) were loaded into a flask
(10 mL). DMF (2 mL) and K2CO3 (207 mg, 1.5 mmol, 3.0 equiv) were then added, which was followed
by the addition of 3-meth◦yl-2-butenyl bromide 2e (0.525 mmol, 1.05 equiv). Then, the reaction
mixture was stirred at 80 C for 6 h under an Ar atmosphere. After completion of the reaction,
as confirmed by TLC, the reaction mixture was cooled down to room temperature and 10 mL of
CH2Cl2 and 10 mL of water were added. After separation of the dichloromethane layer from the
water, the aqueous phase was extracted with CH2Cl2 (2
layers were then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to yield
the crude product. The crude product was purified by silica gel column chromatography with
×
5 mL) again. The combined organic
hexane/EtOAc (8:1 v/v) to afford the desired compound,
4
(CAS: 23676-18-8), as a slightly yellow
1
solid (96 mg, 91% yield). H-NMR (300 MHz, CDCl3,
δ ppm): 7.94–8.01 (m, 3H), 7.69 (t, J = 6.1 Hz,
1H), 7.58 (t, J = 6.1 Hz, 1H), 7.49 (dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 5.85 (t, J = 6.2 Hz,
1H, -CH=C), 4.83 (d, J = 9.1 Hz, 2H, -CH2-), 2.06 (s, 3H, -CH3), 1.99 (s, 3H, -CH3); 13C-NMR (75 MHz,
CDCl3, δ ppm): 156.7, 137.6, 134.4, 129.2, 127.4, 126.5, 126.1, 123.3, 119.6, 118.9, 115.2, 106.4, 64.4, 25.6,
17.9; MS (ESI): m/z = 213.1 [M + H]+; Rf = 0.7 (DCM:MeOH 100:1).
3-(Naphthalen-2-yloxy)propan-1-ol (5). Phenyl ester 1i (0.5 mmol) was loaded into a flask (10 mL).
DMF (2 mL) and K2CO3 (207 mg, 1.5 mmol, 3.0 equiv) were then added, which was followed by t◦he
addition of 3-bromo-1-propanol 2a (2.0 mmol, 4 equiv). Then, the reaction mixture was stirred at 80 C
for 6 h under an Ar atmosphere. After completion of the reaction, as confirmed by TLC, the reaction
mixture was cooled down to room temperature and 10 mL of CH2Cl2 and 10 mL of water were added.

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After separation of the dichloromethane layer from the water, the aqueous phase was extracted with
CH2Cl2 (2 5 mL) again. The combined organic layers were then dried over anhydrous Na2SO4,
×
filtered, and concentrated under vacuum to yield the crude product. The crude product was purified
by silica gel column chromatography with hexane/EtOAc (4:1 v/v) to afford the desired compound,
1
5 (CAS: 7598-29-0), as a slightly yellow oil (96 mg, 95% yield). H-NMR (300 MHz, CDCl3, δ ppm):
7.74–7.82 (m, 3H), 7.48 (t, J = 6.2 Hz, 1H), 7.38 (t, J = 6.2 Hz, 1H), 7.19–7.24 (m, 2H), 4.63 (br s, 1H, -OH)
,
4.22 (t, J = 6.1 Hz, 2H), 4.05 (t, J = 6.1 Hz, 2H), 2.16–2.19 (m, 2H); MS (ESI): m/z = 203.1 [M + H]+;
Rf = 0.4 (DCM:MeOH 50:1).
Butyl 4-methoxybenzoate (10). Compound 10 (CAS: 6946-35-6) was prepared from 1v and 1-butanol (2f),
following the above general procedure and purified by silica gel column chromatography (DCM:MeOH
100:1) to provide the pure compound (59 mg, 57%) as a light oil. 1H-NMR (300 MHz, CDCl3,
δ
ppm):
8.01 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 4.30 (t, J = 6.2 Hz, 2H), 3.85 (s, 3H, -OCH3)
,
1.74 (m, 2H),
1.49 (m, 2H), 0.98 (t, J = 6.2 Hz, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 165.9, 162.7, 131.0, 122.4, 113.0,
64.0, 54.8, 30.3, 18.7, 13.2; MS (ESI): m/z = 209.1 [M + H]+; Rf = 0.8 (DCM:MeOH 100:1).
5-Hydroxy-8-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl acetate (7-acetyl wogonin). 5-Acetyl wogonin (65 mg,
0.2 mmol) were loaded into a flask (25 mL). DMF (1.5 mL) an◦d K2CO3 (82 mg, 0.6 mmol, 3.0 equiv)
was added. Then, the reaction mixture was stirred at 80 C for 6 h under an Ar atmosphere.
After completion of the reaction, as confirmed by TLC, the reaction mixture was cooled down to
room temperature and 5 mL of CH2Cl2 and 5 mL of water were added. After separation of the CH2Cl2
layer from the water, the aqueous phase was extracted with CH2Cl2 (2
×
3 mL) again. The combined
organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum
to yield the crude product. The crude product was purified by silica gel column chromatography
with hexane/EtOAc (5:1 v/v) to afford 7-acyl wogonin (CAS: 95480-80-1) as slightly yellow solids
1
0
δ ppm): 12.49 (s, 1H, 5-OH), 7.99–8.02 (m, 2H, H-2 ,
(56 mg, 86% yield). H-NMR (300 MHz, DMSO-d6,
H-60), 7.63–7.69 (m, 3H, H-30, H-40, H-50), 6.73 (s, 1H, H-3), 6.38 (s, 1H, H-6), 3.81 (s, 3H, 8-OCH3),
2.19 (s, 3H, -CH3); MS (ESI): m/z = 325.1 [M − H]−; Rf = 0.3 (DCM:MeOH 100:1).
4. Conclusions
In summary, we have developed a facile and unified one-pot synthesis to obtain aryloxyalkyl
esters from readily available phenolic esters and suitable substituted halogenated alcohols, which helps
to quickly build a diversity chain of aromatic alkyl esters. In the mechanistic studies, we discovered the
acyl transfer mechanism and explained the reasons for the formation of aryloxyalkyl esters. However,
for secondary alcohols or tertiary alcohols, the corresponding target compounds cannot be obtained
under standard reaction conditions, which can be attributed to the large steric hindrance near the
hydroxyl group affecting the nucleophilic substitution reaction (SN2) of hydroxyl groups. In addition,
secondary or tertiary alcohols are more likely to undergo elimination reactions under alkaline
conditions. Further detailed mechanistic studies and applications will be reported in due course.
Supplementary Materials: The following are available online, characterization data: HRMS, 1H-NMR,
and 13C-NMR spectra of all new compounds.
Author Contributions: F.F. and W.Q. conceived and designed the experiments; X.J. and J.Z. performed the
experiments; J.X. analyzed the data X.J., Y.Z., and H.S. wrote the paper.
Funding: This research was funded by the National Natural Science Foundation of China (Nos. 81502950 and
81703382) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
Acknowledgments: We are grateful to Qi Li for the touch of the manuscript. Special thanks should go to editors
and reviewers who have put considerable time and effort into their kindly comments on the draft.
Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 3aa–3bb are available from the authors.
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